Left Kidney

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2020, Case 15, and is xanthogranulomatous pyelonephritis (kidney). The information provided in this case was accurate and correct at the time of publication in 2020. Any changes in terminology since the time of publication may not be reflected in this case.

Histologic sections show nodules composed of clusters of foamy histiocytes with abundant clear cytoplasm. Inflammation, including microabscess formation, is also noted in some of the sections. The surrounding kidney shows chronic inflammation and renal tubular atrophy, consistent with chronic pyelonephritis. The morphologic findings are consistent with xanthogranulomatous pyelonephritis (XGP).

XGP is a destructive inflammatory process resulting from long-term urinary tract obstruction and infection. It accounts for 0.6% of histologically documented cases of chronic pyelonephritis and 19.2% of nephrectomies performed for pyelonephritis. XGP is usually accompanied by chronic obstruction, calculi, and recurrent urinary tract infections and occurs more frequently in patients with underlying systemic diseases, such as diabetes mellitus, rheumatoid arthritis, chronic viral hepatitis C, cirrhosis, and obesity. The incidence is higher in females and, although it has been described in a vast age range from children to the elderly, usually occurs in the 5th or 6th decade. Patients are almost always symptomatic, and the typical symptoms include urinary tract symptoms, gross hematuria, fever, flank pain, weight loss, and palpable mass. Laboratory findings include leukocytosis and anemia. Urinalysis usually shows pyuria, and urine culture is frequently positive for causal organisms including; Gram-negative bacteria such as Escherichia coli, Proteus, Klebsiella, and Pseudomonas. Imaging with computed tomography shows diffuse disease in the majority of cases, with enlargement of the kidney; hydronephrosis, renal calculus, pyonephrosis, renal cortical atrophy, and abscess are other commonly observed findings.

Grossly, XGP may involve the kidney in a focal, segmental, or diffuse manner. Single to multiple irregular yellow-orange nodules may be seen chiefly in the renal medulla, surrounding a dilated pelvicalyceal system; however, these nodules may extend into the renal parenchyma or invade the ureter or perinephric fat, mimicking tumor nodules. These nodules may exhibit necrosis and abscess. The cortex is usually atrophic. Hydronephrosis, pyonephrosis, and renal calculi are usually identified.

Microscopically, nests, sheets, and clusters of foamy histiocytes (xanthoma cells) are present. The histiocytes typically have clear cytoplasm; however, focal eosinophilic cytoplasm may be present. The xanthomatous cells and macrophages are positive for alpha-1 antitrypsin and lysozyme. A mixed inflammatory infiltrate is usually seen, composed of lymphocytes, plasma cells, neutrophils, and multinucleated giant cells. Microabscess formation may occur. The background kidney usually shows features of chronic pyelonephritis: renal tubular atrophy, fibrosis, and chronic inflammation. Immunohistochemistry is typically not necessary in making the diagnosis of XGP.

Patients may be treated with antibiotics for XGP. If this does not work, the patient may require nephrectomy. For localized lesions, partial nephrectomy may be an option. Nephrectomy is curative if XGP is unilateral; however, any underlying illness causing urinary tract obstruction should be investigated. The prognosis is considered good after treatment.

XGP is frequently misdiagnosed preoperatively because it may mimic other benign and neoplastic conditions. Final diagnosis is usually made based on morphologic and gross examination of a nephrectomy specimen. Other entities that may enter the differential diagnosis include lipomatosis, renal cell carcinoma (RCC), renal malakoplakia (RM), acute pyelonephritis with abscess, and tuberculosis.

Renal malakoplakia morphologically resembles XGP in that it is also an inflammatory mass-like lesion composed of numerous histiocytes. The histiocytes in RM have more eosinophilic cytoplasm and usually have numerous Michaelis–Gutmann bodies, which are calcified, concentric cytoplasmic inclusions that are highlighted by Prussian blue iron stain, PAS, and von Kossa stains. Both lesions may also show a mixed inflammatory cell population and associated multinucleated giant cells. Both lesions may also invade into the kidney parenchyma, be multifocal, and show fibrosis. RM is caused by defective digestion of bacteria by macrophages, leading to accumulation of partially digested bacteria upon which calcium and iron deposit, forming the characteristic Michaelis–Gutmann bodies. RM is much less common than XGP and may present with more severe symptoms of acute or end-stage renal failure.

Xanthomatous cells in XGP may mimic both the clear cells of clear cell RCC and the foamy histiocytes seen in papillary RCC. The presence of an inflammatory infiltrate is a clue that the diagnosis may be XGP. RCC also shows more nuclear irregularities and hyperchromasia than those in XGP. Adequate sampling to reveal the delicate vasculature of clear cell RCC or the papillary structures of papillary RCC usually facilitates the diagnosis; however, as renal biopsy is increasingly used for diagnosis of renal masses, sometimes immunohistochemistry may be necessary for a diagnosis in a limited sample. Cytokeratin and EMA positivity confirm a diagnosis of RCC, whereas histiocyte-specific marker expression (CD68, CD163) is seen in XGP.

Lipomatosis, or renal replacement lipomatosis, may also show clear cells infiltrating the kidney, but this is due to replacement of atrophic kidney by adipocytes. Immunohistochemistry may aid in the diagnosis, if necessary. Adipocytes are positive for S100 and negative for histiocyte-specific markers.

Acute pyelonephritis with abscess overlaps with XGP in etiology, symptoms, and morphology, as both are associated with patients who have immunocompromising illnesses such as diabetes, and both may be caused by urinary tract infection or obstruction. In addition, both may show focal abscess formation within the kidney. Renal abscess, however, is typically focal or may show a wedge-shaped area of necrosis. Renal abscesses are usually based in the cortex, and the inflammatory infiltrate predominantly consists of neutrophils rather than histiocytes.

The genitourinary tract is the second most common site of tuberculosis infection after the lung. Renal tuberculosis shows multiple necrotic cavities within the renal parenchyma that may mimic the nodules of histiocytes seen in XGP. Tuberculosis shows nodules of caseous necrosis with granulomas and Langhans giant cells. Special stains or even PCR for acid-fast bacilli aid in the diagnosis.

1. Which of the following is thought to be the cause of renal malakoplakia rather than xanthogranulomatous pyelonephritis?
   
   
   1. Chronic renal obstruction
   2. Defective macrophage digestion of bacteria
   3. Proteus infection
   4. Staghorn renal calculi
   5. Underlying systemic disease
2. Which of the following special stains is typically positive in xanthogranulomatous pyelonephritis?
   
   
   1. AFB
   2. GMS
   3. Lysozyme
   4. Prussian blue iron
   5. von Kossa
3. Which of the following histologic features is characteristic of xanthogranulomatous pyelonephritis but not renal cell carcinoma?
   
   
   1. Cells with abundant clear cytoplasm
   2. Delicate vasculature
   3. Fibrovascular cores
   4. Foamy histiocytes
   5. Mixed inflammatory infiltrate

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2. Korkes F, Favoretto RL, Bróglio M, Silva CA, Castro MG, Perez MD. Xanthogranulomatous pyelonephritis: clinical experience with 41 cases. Urology. 2008;71(2):178-180.
3. Li L, Parwani AV. Xanthogranulomatous pyelonephritis. Arch Pathol Lab Med. 2011;135(5):671-674.
4. Malek RS, Elder JS. Xanthogranulomatous pyelonephritis: a critical analysis of 26 cases and of the literature. J Urol. 1978;119(5):589-593.
5. Tamboli P, Ro JY, Amin MB, Ligato S, Ayala AG. Benign tumors and tumor-like lesions of the adult kidney. Part II: Benign mesenchymal and mixed neoplasms, and tumor-like lesions. Adv Anat Pathol. 2004;7(1):47-66.

1. Defective macrophage digestion of bacteria (b)
2. Lysozyme (c)
3. Mixed inflammatory infiltrate (e)